This application is for continued support in one of the twelve Retardation Centers initially funded. It is composed of three projects which have as their primary goal to understand the biochemical defects in a number of genetic disorders which can result in mental retardation and early death. The three principal investigators are linked through their constant interaction, exchange of methods and equipment, common tissue culture facilty and goals. Project 1 is concerned with understanding Gaucher disease and other lysosomal disorders through studies on glucocerebrosidase from control and patient tissues, by isolation and characterization of sphingolipid activator proteins and development of new methods for diagnosing and prognosing certain lipid storage disease. These studies will provide new information which will help us to understand and eventually treat this group of diseases. Project 2 is concerned with understanding the defects in four inborn errors of metabolism. These include glutaric acidemia, long- and medium-chain fatty acyl-CoA dehydrogenase deficiencies and glutaric acidemia Type II. The research will develop new methods for diagnosis and for detection of genetic complementation, purify human glutaryl-CoA dehydrogenase and prepare antibodies to it so that genetic heterogeneity in patients can be examined and investigate electron transfer flavoprotein (ETF) and ETF dehydrogenase in controls and patients with glutaric acidemia Type II. Project 3 will examine the reasons for the clinical heterogeneity in patients with glycerol kinase deficiency. The subcellular compartmentation of this enzyme will be studied, with special emphasis on the role of porin, a pore-forming protein on the outer mitochondrial membrane which has been demonstrated to bind hexokinase and glycerol kinase. These proteins will be purified and antibodies to them will be prepared. Studies on the mutant proteins in patients will be done to understand the nature of the defects and the relationship to the clinical features observed. These three projects all share a common goal of understanding normal cellular metabolism and of finding the nature of the mutations in patients with certain genetic diseases so that a rational approach to therapy can be developed.